Short chain fatty acids (SCFAs), such as butyrate (NaB), are derived from fermentation of dietary fiber and present at very high levels in the colon. In vitro, SCFAs induce colonic carcinoma cell maturation (cell cycle arrest, lineage specific differentiation and apoptosis) at concentrations that are at least an order of magnitude lower than those found in the colonic lumen. Therefore, whereas it is likely that SCFAs naturally suppress development and/or progression of colon cancer by mediating colonic epithelial cell maturation, this suppression can clearly fail since colon cancer is a prevalent disease. Our extensive prior work has demonstrated that, besides butyrate's HDAC inhibiting activity, its mitochondrial [unreadable]-oxidation by colonic epithelial cells is necessary for its complete induction of colonic carcinoma cell maturation in vitro. We showed this is also true in vivo by using a mouse with a homozygous genetic inactivation of short chain acyl dehydrogenase (Scad), which encodes the first step in [unreadable]-oxidation of SCFAs. In Scad-/- mice, apoptosis was suppressed greater than 90% in the proximal colon, but not in the small intestine, consistent with the fact that colonic cells are normally exposed to high levels of SCFAs and have integrated their metabolism into regulation of tissue homeostasis. In contrast, small intestinal cells, not normally exposed to these higher levels of SCFAs, do not utilize these compounds in the same way. [unreadable] [unreadable] Recently, we and our collaborators have established novel mouse genetic models that initiate colon [unreadable] cancer in the large intestine, rather than in the small intestine - the site of tumor formation [unreadable] consistently found in mice that inherit a constitutive mutation of the Apc gene. Consequently, we are [unreadable] now in a unique position to use a genetic approach to prove that SCFAs suppress tumor formation in [unreadable] the colon, the site at which they induce cell maturation in vivo. Both an Apcflox/+ mouse, in which the [unreadable] floxed Apc allele is excised by a CDX2:cre transgene targeted to the colon, and the Muc2-/- mouse, [unreadable] develop colon tumors. The Scad-/- mutation will be introduced into each of these models to abrogate [unreadable] SCFA metabolism in order to determine how this alters homeostasis of the intestinal mucosa and [unreadable] tumor development. Moreover, we have demonstrated that the mitochondrial membrane potential [unreadable] (??m) is fundamental in regulating colonic cell maturation pathways, and recently reported that [unreadable] stable elevations in the ??m are linked to reduced response of cells to NaB, but enhanced invasive [unreadable] and metastatic phenotypes in vitro. Therefore, we hypothesize that abrogation of the ability of [unreadable] colonic epithelial cells to undergo maturation pathways in vivo, by introduction of the Scad-/- mutation [unreadable] into the Apcflox/+ and Muc2-/- models, will lead to more aggressive tumors and progression to the [unreadable] metastatic phenotype, the latter not yet achieved for genetically initiated colon cancer. [unreadable] [unreadable] [unreadable]